HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

Ren, Shuling; Gaykalova, Daria A.; Guo, Theresa; Favorov, Alexander V.; Fertig, Elana J.; Tamayo, Pablo; Callejas‐Valera, Juan Luis; Allevato, Michael; Gilardi, Mara; Santos, Jéssica Luana Dos; Fukusumi, Takahito; Sakai, Akihiro; Ando, Mizuo; Sadat, Sayed; Liu, Chao; Xu, Guiyin; Fisch, Kathleen M.; Wang, Zhiyong; Molinolo, Alfredo A.; Gutkind, J. Silvio; Ideker, Trey; Koch, Wayne M.; Califano, Joseph A.

doi:10.1038/s41388-020-01431-8

Cited by 67 publications

(65 citation statements)

References 54 publications

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“…In HPV-associated HNSCC, Ren et al reported that different expression patterns of HPV genes are correlated with the integration status of the virus [ 95 ]. In 69 HPV-associated HNSCC cases in the TCGA dataset, those with HPV integration (+) disease showed a high expression of E6/E7 and low expression of E2/E4/E5, whereas those with HPV integration (−) disease showed a high expression of E2/E4/E5 and low expression of E6/E7.…”

Section: What Induces High Dna Methylation Subtypes?mentioning

confidence: 99%

DNA Methylation and HPV-Associated Head and Neck Cancer

et al. 2021

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Head and neck squamous cell carcinoma (HNSCC), especially oropharyngeal squamous cell carcinoma (OPSCC), has recently been found to be significantly associated with human papillomavirus (HPV) infection. The incidence of OPSCC has been increasing and surpassed the number of cervical cancer cases in the United States. Although HPV-associated OPSCC has a relatively better prognosis than HPV-negative cancer, approximately 20% of HPV-associated HNSCC patients show a poor prognosis or therapeutic response, and the molecular mechanism behind this outcome in the intermediate-risk group is yet to be elucidated. These biological differences between HPV-associated HNSCC and HPV-negative HNSCC are partly explained by the differences in mutation patterns. However, recent reports have revealed that epigenetic dysregulation, such as dysregulated DNA methylation, is a strikingly common pathological feature of human malignancy. Notably, viral infections can induce aberrant DNA methylation, leading to carcinogenesis, and HPV-associated HNSCC cases tend to harbor a higher amount of aberrantly methylated DNA than HPV-negative HNSCC cases. Furthermore, recent comprehensive genome-wide DNA-methylation analyses with large cohorts have revealed that a sub-group of HPV-associated HNSCC correlates with increased DNA methylation. Accordingly, in this review, we provide an overview of the relationship between DNA methylation and HPV-associated HNSCC.

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Section: What Induces High Dna Methylation Subtypes?mentioning

confidence: 99%

DNA Methylation and HPV-Associated Head and Neck Cancer

et al. 2021

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“…These observations imply that viral replication may involve DNA structure complexity that requires DNA repair to proceed. A plurality of HPV-associated cancers maintains episomal DNA copies of HPV genomes, which could be replication-competent [ 2 , 3 , 32 , 33 ], and E2, E4, and E5 can remain expressed in some HPV+ cancers [ 73 ]. How replication competence affects overall DSBR in HPV+ tumors is unclear, and a worthwhile comparison would be episomal only vs. integrated HPV+ cancers in terms of sensitivity to DNA damaging agents and DSBR pathway utilization.…”

Section: Proposed Mechanisms For Increased Radiosensitivity In Hpv+ Tumorsmentioning

confidence: 99%

Genomic Signatures in HPV-Associated Tumors

Hussain

Lundine

Leeman

et al. 2021

Viruses

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Papillomaviruses dysregulate the G1/S cell cycle transition in order to promote DNA synthesis in S phase, which is a requirement for viral replication. The human papillomaviruses (HPV) E6 and E7 oncoproteins mediate degradation of the cell cycle regulators p53 and Rb, which are two of the most universally disrupted tumor-suppressor genes in all of cancer. The G1/S checkpoint is activated in normal cells to allow sufficient time for DNA repair in G1 before proceeding to replicate DNA and risk propagating unrepaired errors. The TP53 pathway suppresses a variety of such errors, including translocation, copy number alterations, and aneuploidy, which are thus found in HPV-associated tumors similarly to HPV-negative tumors with other mechanisms of TP53 disruption. However, E6 and E7 maintain a variety of other virus–host interactions that directly disrupt a growing list of other DNA repair and chromatin remodeling factors, implying HPV-specific repair deficiencies. In addition, HPV-associated squamous cell carcinomas tumors clinically respond differently to DNA damaging agents compared to their HPV negative counterparts. The focus of this review is to integrate three categories of observations: (1) pre-clinical understanding as to the effect of HPV on DNA repair, (2) genomic signatures of DNA repair in HPV-associated tumor genomes, and (3) clinical responses of HPV-associated tumors to DNA damaging agents. The goals are to try to explain why HPV-associated tumors respond so well to DNA damaging agents, identify missing pieces, and suggest clinical strategies could be used to further improve treatment of these cancers.

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“…In conclusion, the analysis of the effect of HPV infection on the epigenetic landscape of the host cell reveals an intricate network of interactions between viral and host proteins. Finally, while the viral oncoprotein E6 and E7 are the most extensively studied, a recent report from Ren et al investigated the oncogenic role of the episomal expression of the E2, E4 and E5 proteins [203]. Whole genomic expression analysis of pharyngeal and cervical cancers co-expressing E2, E4 and E5 showed a mechanism of carcinogenesis distinct from those found in tumors with HPV integration, and apparently characterized by fibroblast growth factor receptor (FGFR) pathway activation [203].…”

Section: Human Papillomavirus (Hpv)mentioning

confidence: 99%

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

2021

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Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.

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HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

Cited by 67 publications

References 54 publications

DNA Methylation and HPV-Associated Head and Neck Cancer

DNA Methylation and HPV-Associated Head and Neck Cancer

Genomic Signatures in HPV-Associated Tumors

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

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